The present invention relates to nucleotide analog esters, their pharmaceutically acceptable acid addition salts, processes for their production, and to their use.
Compounds related to the nucleotide analogs of the present invention may be found in: U.S. Pat. Nos. 5,043,339, 5,108,994 and 5,166,198; EP 206 459; EP 253 412; EP 269 947; EP 270 885; EP 319 228; EP 343 133; EP 398 231; EP 404 296; EP 465 297; EP 468 119; EP 468 866; EP 479 640; EP 481 214; EP 494 370; EP 531 597; PCT/GB91/01171; PCT/US92/01020; PCT/US92/05208; WO 91/19721; Bronson et al., Bioorg Medicinal Chem Lett (1992) 2:685-690; Bronson et al., J Med Chem (1989) 32:1457-1463; Bronson et al., Nucleotide Analogs as Antiviral Agents, ACS Symposium Series 401, J. C. Martin, Ed., p. 72-87, American Chemical Society, Washington, D.C. (1989); Colla, et al., J Med Chem (1983) 26:602-604; Curley, et al., Antiviral Res (1990) 14:345-356; De Clercq, et al., Nature, (1986) 323:464-467; Farrow, et al., J Med Chem (1990) 33:1400-1406; Farquhar, et al., J. Pharm Sci (1983) 72:324-325; Freed, et al., Biochem Pharmacol (1989) 19:3193-3198; Freeman, et al., J Med Chem (1992) 35:3192-3196; Gabrielsen, B., et al., Antiviral Res Supp I (1992) 17:149; Gumport, et al., Proc Natl Acad Sci (1971) 2559-2563; Juodka, et al., Coll Czech Chem Commun (1974) 39:963-968; Kim, et al., Bioorg Medicinal Chem Lett (1992) 2:367-370; Kim, et al., Tet Lett (1992) 33:25-28; Kim, et al., J Med Chem (1990) 33:1207-1213; Kumar, et al., J Med Chem (1990) 33:2368-2375; McGuigan, et al., Antiviral Chem Chemother (1993) 4:97-101; McGuigan, et al., Antiviral Res (1991) 15:255-263; Rosenberg, et al., Coll Czech Chem Commun (1988) 53:2753-2777; Rosenberg, et al., Coll Czech Chem Commun (1988) 52:2792-2800; Rosenberg, et al., Coll Czech Chem Commun (1988) 52:2801-2808; Starrett, et al., Antiviral Res (1992) 19:267-273; Yu, et al., J Med Chem (1992) 35:2958-2969; Wolff-Kugel, et al., Tet Lett (1991) 32:6341-6344.
A characteristic of nucleotide analogs or nucleotides having a phosphonate or a phosphate group is the presence of one or two negative charges associated with the phosphorus group at physiologic pH. Workers believe the charge associated with moieties such as phosphate or phosphonate groups generally limit oral bioavailability by limiting passive diffusion through the intestine membrane (Liebman, et al., J. Biol. Chem. (1955) 216:823-830; Roll, et al., J Biol Chem, (1956) 220:439-444; Srivastava, et al., Bioorg Chem (1984) 12:118-129; Palu, et al., Antiviral Res (1991) 16:115-119; Sastry, et al., Mol Pharmacol (1992) 41:441-445). Workers often administer these compounds parenterally to obtain therapeutic serum or intracellular levels.